Human interleukin-4 (IL-4) was first cloned and characterized by Yokota et al. Proc. Natl. Acad. Sci. 83:5894 (1986)!. IL-4 is a highly pleiotropic lymphokine which affects many different components of the immune system. It has T cell growth factor (TCGF) activity, and B cell growth factor activity. It is capable of potentiating the TCGF activity of interleukin-2 (IL-2) and the colony-forming activity of granulocyte-macrophage colony stimulating factor (GM-CSF).
It induces the preferential production of IgG.sub.1 and IgE, induces the low affinity receptor for IgE (CD23), and induces the expression of human leukocyte class II DR antigens.
These activities suggest several possible therapeutic uses for IL-4, e.g., as an anti-tumor agent Tepper et al., Cell 57:503 (1989)!, a potentiating agent for IL-2 anticancer therapy, as a potentiating agent for GM-CSF-stimulated bone marrow regeneration, or as an agent to treat bare lymphocyte syndrome Touraine, Lancet, pgs. 319-321 (Feb. 7, 1981); Touraine et al., Human Immunology 2:147 (1981); and Sullivan et al., J. Clin. Invest. 76:75 (1985)!. IL-4 and IL-4 agonists are thus potentially useful therapeutic agents.
The IgE- and CD23-inducing activity of IL-4 could have important consequences for persons suffering from allergic diseases. The availability of IL-4 antagonists could provide an alternative to the use of glucocorticoid steroids, which have many deleterious side effects, especially with prolonged usage Goodman and Gillman, The Pharmacological Basis of Therapeutics, 6th Ed. (MacMillan Publishing Company, New York, 1980)!.
Strongly blocking monoclonal antibodies specific for human IL-4 provide a means for constructing agonists or antagonists by generating anti-idiotype antibodies (U.S. Pat. No. 4,731,237) or by mimotope screening Geysen et al., J. Immunol. Meth. 102:259 (1987); PCT patent applications WO 86/00991 and WO 86/06487!. Because most monoclonal antibodies are of rodent cell origin, however, there is a possibility that they would be immunogenic if used therapeutically in a human being, particularly if used over a long period of time. To avoid this possibility, it would be desirable to have human antibodies, or "humanized" antibodies, against human IL-4.
Initial efforts to reduce the immunogenicity of rodent antibodies involved the production of chimeric antibodies, in which mouse variable regions were fused with human constant regions Liu et al., Proc. Natl. Acad. Sci. USA 84:3439 (1987)!. It has been shown, however, that mice injected with hybrids of human variable regions and mouse constant regions develop a strong anti-antibody response directed against the human variable region. This suggests that in the human system, retention of the entire rodent Fv region in such chimeric antibodies may still give rise to human anti-mouse antibodies.
It is generally believed that CDR loops of variable domains comprise the binding site of antibody molecules, the grafting of rodent CDR loops onto human frameworks (i.e., humanization) was attempted to further minimize rodent sequences Jones et al., Nature 321:522 (1986); Verhoeyen et al., Science 239:1534 (1988)!. Studies by Kabat et al. J. Immunol. 147:1709 (1991)! have shown that framework residues of antibody variable domains are involved in CDR loop support.
It has also been found that changes in framework support residues in humanized antibodies may be required to preserve antigen binding affinity. The use of CDR grafting and framework residue preservation in a number of humanized antibody constructs has been reported, e.g., by Queen et al. Proc. Natl. Acad. Sci. USA 86:10029 (1989)!, Gorman et al. Proc. Natl. Acad. Sci. USA 88:4181 (1991)! and Hodgson Bio/Technology 9:421 (1991)!. Exact sequence information has been reported for only a few humanized constructs.
From the foregoing, it is evident that there is a need for monoclonal antibodies specific for IL-4 that can be used therapeutically. Preferably, these antibodies should be humanized antibodies.